PCSK9 is a critical regulator of the innate immune response and septic shock outcome.
PCSK9 is a critical regulator of the innate immune response and septic shock outcome.
复制标题
DOI：
10.1126/scitranslmed.3008782
复制
发表时间：
2014-10-15
影响因子：
17.1
通讯作者：
Boyd JH
中科院分区：
文献类型：
--
作者：
Walley KR;Thain KR;Russell JA;Reilly MP;Meyer NJ;Ferguson JF;Christie JD;Nakada TA;Fjell CD;Thair SA;Cirstea MS;Boyd JH
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）的活性降低会增加肝细胞上低密度脂蛋白（LDL）受体的数量，从而增加LDL清除率。脂质从病原体中的清除与内源性脂质清除有关;因此，PCSK 9还可调节病原体脂质（如脂多糖（LPS））的清除。与对照组相比，Pcsk 9基因敲除小鼠显示炎性细胞因子产生和对LPS的其他生理反应减少。在人肝细胞中，PCSK 9抑制LPS摄取，这是全身清除和解毒的必要步骤。药理学抑制PCSK 9可改善小鼠多微生物腹膜炎的存活率和炎症。人PCSK 9功能丧失遗传变异体与脓毒性休克患者的生存率改善以及脓毒性休克患者和健康志愿者在LPS给药后炎症细胞因子反应的降低相关。在LDL受体（LDLR）敲除小鼠和对PCSK 9耐药的LDLR变体纯合的人中，PCSK 9效应被消除。总之，我们的研究结果表明，PCSK 9功能降低与通过LDLR增加病原体脂质清除、降低炎症反应和改善脓毒性休克结局相关。
A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of lowdensity lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.
登录
查看更多内容
影响因子：
8.8
作者：
Kumar, Arland;Roberts, Daniel;Cheang, Mary
通讯作者：
Cheang, Mary
DOI：
10.1073/pnas.91.17.7922
发表时间：
1994-08-16
影响因子：
11.1
作者：
GALLAY, P;HEUMANN, D;GLAUSER, MP
通讯作者：
GLAUSER, MP
影响因子：
4.8
作者：
Hailman, E;Albers, JJ;Wright, SD
通讯作者：
Wright, SD
影响因子：
24
作者：
Chen, SN;Ballantyne, CM;Marian, AJ
通讯作者：
Marian, AJ
影响因子：
15.9
作者：
Lagace, Thomas A.;Curtis, David E.;Horton, Jay D.
通讯作者：
Horton, Jay D.